Ceramic particle group and method for production thereof and use thereof

ABSTRACT

A ceramic particle group dispersed in a solvent in a state of primary particles of single crystal, a method for production thereof and a use thereof are disclosed. In one embodiment a method is disclosed for producing a sintered particle (ceramic particle) group of hydroxyapatite (HAp), which includes a step of subjecting a system wherein calcium carbonate is present between primary particles of hydroxyapatite (HAp) to sintering and then dissolving calcium carbonate with water to remove calcium carbonate. A hydroxyapatite (HAp) sintered particle group produced by the above method is a nanometer size particle group having a particle diameter of about 70 to about 120 nm, and is a particle group having a uniform particle diameter (coefficient of variation: 12%), and further 96% of the particle group is dispersed as a single crystal particle.

TECHNICAL FIELD

The present invention relates to highly dispersive ceramic particlesthat exist as primary particles of single crystal in a solvent, andparticularly to a calcium phosphate sintered particle group (ceramicparticle group), as represented by monocrystalline hydroxyapatite, thatis biocompatible, connective and adherent to biological tissues, andthat is not easily decomposed and absorbed in the body, and that isuseful as medical materials. The invention also relates to a producingmethod of such a particle group, and use thereof.

BACKGROUND ART

Due to good biocompatibility, calcium phosphates (hereinafter, referredto as “CaP”), as represented by hydroxyapatite (hereinafter, referred toas “HAp”), are of great interest as biomaterials. For example, calciumphosphates (CaP), and hydroxyapatite (HAp) in particular, have been usedas artificial joints, bone fillers, artificial bones, dental implants,percutaneous devices, and dental filler cements. Further, in order torender bioactivity to a high-molecular medical material such as siliconerubber and polyurethane, calcium phosphate (CaP) such as hydroxyapatite(HAp) is often bonded to such a high-molecular medical material. Otheruses include a filler for chromatography.

When using hydroxyapatite (HAp) or other types of calcium phosphates(CaP) by bonding it to medical material or high-molecular medicalmaterial, or when using hydroxyapatite (HAp) or calcium phosphate (CaP)as a filler for chromatography, it is preferable that these materials beused in sintered form, i.e., in the form of ceramic, in order to improvestability and ensure formability in the body. Further, for uniformcoating of the high-molecular medical material and improved resolutionin chromatography, a small and uniform particle diameter (narrowparticle size distribution) is needed.

Common methods of producing particles of hydroxyapatite (HAp) and othertypes of calcium phosphates (CaP) include a wet method, a hydrothermalmethod, and a dry method, for example. The wet method is predominant inindustrial settings since it allows for mass synthesis. Specificexamples of the wet method are described, for example, in Non-PatentPublication 1, which teaches a precipitation method in which phosphoricacid is dropped into a slurry of calcium hydroxide to produce calciumphosphate, and a hydrolysis method in which calcium phosphate isproduced by the reaction of calcium phosphate dihydrate with calciumcarbonate.

There is also a method in which particles of calcium phosphate (Cap) isdried to produce sintered particles (ceramic particles). This can becarried out by heating at 800° C. to 1200° C., or by a spray dryingmethod, for example, as disclosed in Non-Patent Publications 2 and 3.The spray drying method is a technique in which a dispersion ofparticles, such as a solution or suspension (slurry, etc.) containingeffective substance is atomized and the particles are instantlysolidified by bringing it into contact with a stream of hot air. Morespecifically, a solution or suspension containing primary particles ofcalcium phosphate (CaP) is sprayed in a stream of hot air to form finespherical particles of calcium phosphate.

Non-Patent Publication 4 describes a method in which a source solutioncontaining calcium phosphate is dropped into liquid nitrogen to prepareparticles of calcium phosphate, which are then sintered to producesintered particles of calcium phosphate. This publication also describessintered particles of calcium phosphate, obtained by this method, whoseparticle diameter ranges from 450 μm to 3000 μm.

Non-Patent Publication 5 describes a method in which a drip-castingprocess is used to prepare hydroxyapatite particles, which are thensintered to produce sintered particles of hydroxyapatite. Thispublication also describes sintered particles of hydroxyapatite,obtained by this method, whose particle diameter ranges from 0.7 mm to 4mm.

[Non-Patent Publication 1]

Inorganic Materials, Vol 2 No. 258, 393-400 (1995), ControllingMorphology of Crystals and Crystal Groups of Hydroxyapatite and RelatedPhosphates, Nobuyuki Matsuda, Jo Wakana, Fumihiro Kaji

[Non-Patent Publication 2]

P. Luo and T. G. Nieh Biomaterials, 17, 1959 (1996), Preparinghydroxyapatite powders with controlled morphology

[Non-Patent Publication 3]

L. J. Cummings, P. Tunon, T. Ogawa, Spec. Publ. R. Soc. Chem. 158, 134(1994), Macro-Prep Ceramic Hydroxyapatite—New Life for an OldChromatographic Technique

[Non-Patent Publication 4]

Biomaterials 1994, Vol. 15 No. 6, M. Fabbri, G. C. Celotti and A.Ravaglioli, Granulates based on calcium phosphate with controlledmorphology and porosity for medical applications: physico-chemicalparameters and production technique

[Non-Patent Publication 5]

Biomaterials 1996, Vol. 17 No. 20, Dean-Mo Liu, Fabrication andcharacterization of porous hydroxyapatite granules

The inventors of the present invention have been conducting a study onthe synthesis of a chemically bonded hydroxyapatite (HAp)-polymercomplex, intended for the development of biocompatible devices for usein bio-tissues, and subcutaneous cells and other soft tissues inparticular. In this connection, the inventors have producedmonocrystalline hydroxyapatite particles (ceramic particles) bysintering (pre-baking) at 800° C. This was intended to improvecrystallinity of the hydroxyapatite (HAp) for the purpose of suppressingthe particles from dissolving and decomposing in the body. In order forthe hydroxyapatite (HAp) particles to form strong chemical bonds on thesurface of the high-molecular substrate, the particles need to be welldispersed in the medium when adsorbed by the high-molecular substrate. Aproblem, however, is that the hydroxyapatite (HAp) particles (primaryparticles) fuse together during the sintering process to form irregularsecondary particles. This has resulted in lower dispersibility and areduced specific surface area.

The problem of irregular secondary particles, lower dispersibility andreduced specific surface area also occurs in the method (spray dryingmethod) disclosed in, for example, Non-Patent Publications 2 and 3.Further, with the spray drying method, the particle diameter of thecalcium phosphate (CaP) particles cannot be controlled to a uniform size(particle size distribution cannot be narrowed beyond a certain range).To describe more specifically, in the spray drying method, a solution orsuspension of particles is atomized in a stream of hot air, and thiscauses the fine particles (primary particles) of calcium phosphate (CaP)to fuse together and form secondary particles. Since it is impossible tocontrol the number of fine particles (primary particles) that clustertogether in the stream of hot air, it is not possible with the spraydrying method to accurately control the particle size distribution ofcalcium phosphate (CaP) particles. Thus, when the spray drying method isused to produce ceramic particles of calcium phosphate (CaP), theresulting particles need to be further classified depending on intendeduse. For example, in the case where the ceramic particles of calciumphosphate (CaP) are used as a filler for chromatography, the supportneeds to have a uniform particle diameter (narrow particle sizedistribution) for improved resolution. Thus, when using ceramicparticles of calcium phosphate (CaP) as a filler for chromatography, aceramic particle group of calcium phosphate (CaP) needs to be used thathas a uniform particle diameter (narrow particle size distribution).

Further, with the producing method of a ceramic particle group ofcalcium phosphate as disclosed in, for example, Non-Patent Publications2 and 3, the resulting particle group cannot have a particle diametersmaller than 1 to 8 μm (Non-Patent Publication 2). Further, obtaining aparticle group of a narrow particle size distribution by classifying theceramic particle group of calcium phosphate disclosed in Non-PatentPublication 2 is not feasible due to physical limitations. Indeed, it isvery difficult to reduce the particle size distribution any further andclassification requires large cost.

The present invention was made in view of the foregoing problems, and anobject of the invention is to provide a ceramic particle group that isdispersed in a solvent as primary particles of single crystal, andparticularly a calcium phosphate (CaP) sintered particle group (ceramicparticle group), as represented by monocrystalline hydroxyapatite (HAp),that is biocompatible, connective and adherent to biological tissues,and that is not easily decomposed and absorbed in the body, and that isuseful as medical materials. The invention also provides to a producingmethod of such a particle group, and use thereof.

DISCLOSURE OF INVENTION

The inventors of the present invention diligently worked to solve theforegoing problems and accomplished the present invention.

Specifically, in order to achieve the foregoing objects, the presentinvention provides a ceramic particle group comprised of granularceramic particles, wherein the ceramic particles have a particlediameter in a range of 10 nm to 700 nm, and wherein a coefficient ofvariation of particle diameter of the ceramic particles is no greaterthan 20%.

A ceramic particle group according to the present invention is comprisedof fine particles of a uniform particle diameter (narrow particle sizedistribution). This allows the ceramic particle group to be uniformlyadsorbed on a high-molecular medical material without requiring asophisticated classification or other additional procedures. Further,the ceramic particle group can be used as a chromatography filler thatcan be uniformly charged into a column and provides good resolution anddesirable reproducibility.

In order to achieve the foregoing objects, a ceramic particle groupaccording to the present invention may be adapted so that it iscomprised of granular ceramic particles, and that a majority of theceramic particles in the ceramic particle group are monocrystallineprimary particles, which are either primary particles of single crystal,or a cluster of primary particles of single crystal that are heldtogether by ionic interactions.

In a ceramic particle group according to the present invention, amajority of the ceramic particles are primary particles of singlecrystal that are highly dispersive in a solvent, or a cluster of primaryparticles of single crystal (monocrystalline primary particles) that areheld together by ionic interactions. This makes it easier to adsorb theceramic particle group on the high-molecular medical substrate. Further,since the primary particles are not bonded together, the ceramicparticle group has a large specific surface area, making it suitable asa filler for chromatography. Further, since the ceramic particle groupis very stable and dispersive in a body, it can be used as a medicalmaterial for supporting and releasing drugs.

A ceramic particle group according to the present invention may beadapted so that a proportion of the monocrystalline primary particlescontained in the ceramic particle group is no less than 70%.

According to this arrangement, in a ceramic particle group according tothe present invention, a 70% or greater proportion of the particles areprimary particles of single crystal, or a cluster of primary particlesof single crystal (monocrystalline primary particles) that are heldtogether by ionic interactions. This makes it easier to adsorb theceramic particle group on a high-molecular medical substrate. Further,this makes the ceramic particle group suitable as a chromatographyfiller or a medical material.

A ceramic particle group according to the present invention may beadapted so that the ceramic particles have a particle diameter in arange of 10 nm to 700 nm.

According to this arrangement, a ceramic particle group according to thepresent invention has a small (nanometer size) particle diameter in arange of 10 nm to 700 nm. This allows the ceramic particle group to beuniformly adsorbed on a high-molecular medical material. Further, theceramic particle group can be used as a chromatography filler that canbe uniformly charged into a column and provides good resolution anddesirable reproducibility.

A ceramic particle group according to the present invention may beadapted so that a coefficient of variation of particle diameter of theceramic particle group is no greater than 20%.

A ceramic particle group according to the present invention is comprisedof fine particles of a uniform particle diameter (narrow particle sizedistribution). This allows the ceramic particle group to be uniformlyadsorbed on a high-molecular medical material without requiring asophisticated classification or other additional procedures. Further,the ceramic particle group can be used as a chromatography filler thatcan be uniformly charged into a column and provides good resolution anddesirable reproducibility.

A ceramic particle group according to the present invention may beadapted so that the ceramic particles comprise sintered particles ofcalcium phosphate.

According to this arrangement, a ceramic particle group according to thepresent invention comprises sintered particles of calcium phosphate withgood biocompatibility. This makes ceramic particles according to thepresent invention suitable as a medical material.

A ceramic particle group according to the present invention may beadapted so that the ceramic particles comprise sintered particles ofhydroxyapatite.

According to this arrangement, ceramic particles according to thepresent invention comprise sintered particles of hydroxyapatite withsuperior biocompatibility, making it possible to use the ceramicparticles in a wide variety of applications. This makes the presentinvention even more suitable as materials for medical applications.

In order to achieve the foregoing objects, the present inventionprovides a method for producing a ceramic particle group, the methodincluding: a mixing step of mixing ceramic particles of ceramic materialwith an anti-fusing agent, so as to place the anti-fusing agent betweenthe primary particles of ceramic material to be subjected to sintering;and a sintering step of sintering the mixed particles obtained in themixing step.

According to a producing method of a ceramic particle group according tothe present invention, an anti-fusing agent is placed between theprimary particles of, for example, amorphous calcium phosphate(hydroxyapatite), so that the primary particles do not fuse together inthe next sintering step. As a result, ceramic particles can be producedthat are dispersed in a solvent as primary particles of single crystal,or a cluster of primary particles of single crystal (monocrystallineprimary particles) that are held together by ionic interactions.Further, since the primary particles do not easily form irregularlyshaped secondary particles, the average particle diameter can be keptsmall. It is also possible to provide a uniform particle diameter inceramic particles produced by a producing method of the presentinvention.

In order to achieve the foregoing objects, a producing method of aceramic particle group according to the present invention may be adaptedso that the mixing step is a step in which the primary particles aremixed with a solution that contains a high-molecular compound having anyof a carboxyl group, a sulfuric acid group, a sulfonic acid group, aphosphoric acid group, a phosphonic acid group, and an amino group onside chains, and in which metal salts are added to the mixture of theprimary particles and the high-molecular compound.

Further, in order to achieve the foregoing objects, a producing methodof a ceramic particle group according to the present invention may beadapted so that the high-molecular compound is at least one kind ofsubstance selected from the group consisting of: poly(acrylic acid),poly(methacrylic acid), poly(glutamic acid), poly(ethylene sulfonicacid), poly(sulfoalkyl methacrylate), poly(acrylamido-N-methylphosphonicacid), and polypeptide.

Further, in order to achieve the foregoing object, a producing method ofa ceramic particle group according to the present invention may beadapted so that the metal salts comprise alkali metal salts and/oralkali earth metal salts and/or transition metal salts.

According to a producing method of a ceramic particle group according tothe present invention, the high-molecular compound is adsorbed onsurfaces of the primary particles of, for example, amorphous calciumphosphate (hydroxyapatite), so that any of the carboxyl group, sulfuricacid group, sulfonic acid group, phosphoric acid group, phosphonic acidgroup, and amino group is introduced on the surfaces of the primaryparticles. The carboxyl group, sulfuric acid group, sulfonic acid group,phosphoric acid group, phosphonic acid group, or amino group is presentan ions in a solvent, and therefore by adding metal salts (alkali metalsalts and/or alkali earth metal salts and/or transition metal salts), itis possible to generate carboxylate, sulfate, sulfonate, phosphate,phosphonate, or an amino acid salt of the metals (alkali metal and/oralkali earth metal and/or transition metal) on the surfaces of theprimary particles. The metal salts serve as the anti-fusing agent.

According to this arrangement, the presence of the high-molecularcompound on the surfaces of the primary particles ensures that theprimary particles do not come into contact one another. The primaryparticles are therefore prevented from fusing together in the sinteringstep, and ceramic particles can be produced that are dispersed in asolvent as primary particles of single crystal, or a cluster of primaryparticles of single crystal (monocrystalline primary particles) that areheld together by ionic interactions. Further, since the primaryparticles do not easily form irregularly shaped secondary particles, theaverage particle diameter can be kept small. It is also possible toprovide a uniform particle diameter in ceramic particles produced by aproducing method of the present invention.

A producing method of a ceramic particle group according to the presentinvention may be adapted so that the anti-fusing agent is non-volatileat a sintering temperature of the sintering step.

The anti-fusing agent used in a producing method of a ceramic particlegroup according to the present invention is non-volatile at a sinteringtemperature of the sintering step. Thus, the anti-fusing agent betweenthe source particles will not be lost during the sintering step, andensures that the primary particles do not fuse together.

A producing method of a ceramic particle group according to the presentinvention may be adapted to further include a removing step of removingthe anti-fusing agent after the sintering step.

According to this arrangement, the anti-fusing agent in the mixture canbe removed from the ceramic particle group.

Further, a producing method of a ceramic particle group according to thepresent invention may be adapted so that the removing step includes astep of dissolving the anti-fusing agent in a solvent.

According to this arrangement, the ceramic particles containing theanti-fusing agent, produced by sintering, are suspended to a solvent todissolve the anti-fusing agent. By filtering the suspension for example,the anti-fusing agent can easily be removed from the ceramic particlegroup.

A producing method of a ceramic particle group according to the presentinvention may be adapted so that the solvent used in the removing stepdissolves the anti-fusing agent but does not dissolve the ceramicparticles.

According to this arrangement, the solvent used for the removal of theanti-fusing agent dissolves only the anti-fusing agent. This enables theanti-fusing agent to be reliably removed from the ceramic particlegroup, without damaging the ceramic particles.

Further, a producing method of a ceramic particle group according to thepresent invention may be adapted so that the anti-fusing agent issoluble in an aqueous solvent.

By using an anti-fusing agent that dissolves in an aqueous solvent, theanti-fusing agent (calcium carbonate) can be removed only by suspendingthe ceramic particles in an aqueous solvent such as deionized water.Since the organic solvent is not used in the removing step, the removingstep does not require equipment used for the removal procedure involvingorganic solvent, nor does it require the waste disposal process for theorganic solvent. That is, the anti-fusing agent can more easily beremoved from the ceramic organic group.

A producing method of a ceramic particle group according to the presentinvention may be adapted so that the anti-fusing agent is calciumcarbonate.

Calcium carbonate is water-soluble. Thus, the anti-fusing agent (calciumcarbonate) can be removed only by suspending the ceramic particle groupin an aqueous solvent such as deionized water. Since the organic solventis not used in the removing step, the removing step does not requireequipment used for the removal procedure involving organic solvent, nordoes it require the waste disposal process for the organic solvent. Thatis, the anti-fusing agent can more easily be removed from the ceramicorganic group.

Further, a producing method of a ceramic particle group according to thepresent invention may be adapted to include a primary particlegenerating step of generating primary particles before the mixing step.

By obtaining primary particles in the primary particle generating stepand performing the mixing step and the sintering step of the presentinvention using the primary particles, ceramic particles with superiordispersibility can be produced.

A producing method of a ceramic particle group according to the presentinvention may be adapted so that the primary particles generated in theprimary particle generating step have a particle diameter in a range of10 nm to 500 nm.

By obtaining nanometer size primary particles in the primary particlegenerating step and performing the mixing step and the sintering step ofthe present invention using the primary particles, nanometer sizeceramic particles can be produced that dissolve in a solvent as primaryparticles of single crystal, or a cluster of primary particles of singlecrystal (monocrystalline primary particles) that are held together byionic interactions.

Further, a producing method of a ceramic particle group according to thepresent invention may be adapted so that a coefficient of variation ofparticle diameter of a primary particle group comprised of the primaryparticles generated in the primary particle generating step is nogreater than 20%.

By obtaining primary particles of a uniform particle diameter (narrowparticle size distribution) in the primary particle generating step andperforming the mixing step and the sintering step of the presentinvention using the primary particles, ceramic particles of a uniformparticle diameter can be produced that are dispersed in a solvent asprimary particles.

In order to achieve the foregoing objects, a chromatography filleraccording to the present invention uses a ceramic particle groupaccording to the present invention.

A chromatography filler according to the present invention uses aceramic particle group according to the present invention, and thereforehas a uniform particle diameter (narrow particle size distribution). Itis therefore possible to produce a chromatography filler that has alarge specific surface area and good resolution. Further, due to ananometer size particle diameter, the chromatography filler can have alarge filling factor for the column, good resolution, and desirablereproducibility.

In order to achieve the foregoing objects, a dental or medical materialaccording to the present invention uses a ceramic particle groupaccording to the present invention.

Since a ceramic particle group of the present invention is used, amedical material according to the present invention exists as primaryparticles of single crystal with superior dispersibility in a solvent,or a cluster of such primary particles of single crystal(monocrystalline primary particles) that are held together by ionicinteractions. This makes it easier to adsorb the medical material on thehigh-molecular medical substrate. Further, by using ceramic particles ofcalcium phosphate (HAp, etc.) with superior biocompatibility, dental ormedical materials can be produced that have superior biocompatibility.

The present invention therefore provides a ceramic particle group thatis dispersed in a solvent as non-coagulating primary particles of singlecrystal, or a cluster of such primary particles of single crystal(monocrystalline primary particles) that are held together by ionicinteractions. More specifically, the present invention provides asintered particle (ceramic particle) group of calcium phosphate (CaP),as represented by monocrystalline hydroxyapatite (HAp), that isbiocompatible, connective and adherent to biological tissues, and thatis not easily decomposed and absorbed in the body, and that is useful asmedical materials. The invention also provides a nanometer size ceramicparticle group.

A ceramic particle group according to the present invention can easilybe adsorbed on a high-molecular medical substrate such as silicone orpolyurethane. Further, since the primary particles do not fuse together,a ceramic particle group according to the present invention has a largespecific surface, making it suitable as a filler for chromatography.Further, since the ceramic particle group is very stable and dispersivein a body, it can be used as a medical material for supporting andreleasing drugs.

In order to achieve the foregoing objects, a cosmetic additive, abuilding material, or an industrial material according to the presentinvention uses a ceramic particle group according to the presentinvention.

Non-Patent Publication 1 describes common producing methods (wet method,hydrothermal method, dry method, etc.) of calcium phosphate (CaP)particles, as well as shapes or other properties of CaP particlesobtained by such common producing methods. However, Non-PatentPublication 1 does not disclose using an anti-fusing agent as in aproducing method of a ceramic particle group according to the presentinvention, nor does it disclose primary particles of a particle diameterranging from 10 nm to 700 nm as in a ceramic particle group according tothe present invention.

Non-Patent Publication 2 describes a producing method of hydroxyapatite(HAp) particles using a spray drying method, in order to control shapesof the hydroxyapatite (HAp) particles. However, unlike a producingmethod of a ceramic particle group according to the present invention,the method disclosed in Non-Patent Publication 2 does not prevent fusionof the primary particles, and as such the primary particles fusetogether to form irregularly shaped secondary particles. This has led topoor dispersibility and reduced specific surface area. Further, with theproducing method of Non-Patent Publication 2, the particle diameter ofthe calcium phosphate (CaP) particles cannot be controlled to a uniformsize (particle size distribution cannot be narrowed beyond a certainrange).

Non-Patent Publication 3 describes ceramic particles (hydroxyapatiteparticles) with particle diameters of 20 μm, 40 μm, and 80 μm. Thisgreatly differs from the particle diameters 10 nm to 700 nm of a ceramicparticle group according to the present invention.

Non-Patent Publication 4 describes a method in which a source solutioncontaining calcium phosphate is dropped into liquid nitrogen to prepareparticles of calcium phosphate, which are then sintered to producesintered particles of calcium phosphate. This publication also describessintered particles of calcium phosphate, obtained by this method, whoseparticle diameter ranges from 450 μm to 3000 μm.

However, in the producing method of Non-Patent Publication 4, sinteringis performed without the anti-fusing agent as used in a producing methodof a ceramic particle group according to the present invention. This hascaused the primary particles to fuse together and form irregularlyshaped secondary particles, and led to poor dispersibility and reducedspecific surface area. A ceramic particle group of the present inventionexists as primary particles with a particle diameter of 10 nm to 700 nm.This greatly differs from that described in Non-Patent Publication 4.

Non-Patent Publication 5 describes a method in which a drip-castingprocess is used to prepare hydroxyapatite particles, which are thensintered to produce sintered particles of hydroxyapatite. Thispublication also describes sintered particles of hydroxyapatite,obtained by this method, whose particle diameter ranges from 0.7 mm to 4mm.

However, the producing method described in Non-Patent Publication 5 doesnot use the anti-fusing agent as used in a producing method of a ceramicparticle group according to the present invention. Further, since themethod controls the particle diameter of the hydroxyapatite particlesaccording to the size of pore or model of the pipette, it cannot producea ceramic particle group with a nanometer size particle diameter of 10nm to 700 nm as in the present invention. The teaching of Non-PatentPublication 5 greatly differs from that of the present invention.

Additional objects, features, and strengths of the present inventionwill be made clear by the description below. Further, the advantages ofthe present invention will be evident from the following explanation.

BRIEF DESCRIPTION OF DRAWINGS

FIG. 1 is a scanning electron micrograph (SEM) of a sintered particlegroup of hydroxyapatite (HAp) obtained in Example 1.

FIG. 2 is a scanning electron micrograph (SEM) of a sintered particlegroup of hydroxyapatite (HAp) obtained in Comparative Example 1.

FIG. 3( a) is a graph representing a result of measurement, as measuredby a dynamic light scattering method on particle size distribution ofthe sintered particle group of hydroxyapatite (HAp) obtained in Example1.

FIG. 3( b) is a graph representing a result of measurement, as measuredby a dynamic light scattering method on particle size distribution ofthe sintered particle group of hydroxyapatite (HAp) obtained inComparative Example 1.

FIG. 4 is a chart showing results of x-ray diffraction performed on thesinter particles of hydroxyapatite (HAp) obtained in Example 1 andComparative Example 1.

FIG. 5 is a chart showing results of FT-IR performed on the sinteredparticles of hydroxyapatite (HAp) obtained in Example 1 and ComparativeExample 1.

FIG. 6 is a graph representing a result of measurement, as measured by adynamic light scattering method on particle size distribution of thesintered particle group of hydroxyapatite (HAp) obtained in a primaryparticle generating step of Example 2.

FIG. 7 is a graph representing a result of measurement, as measured by adynamic light scattering method on particle size distribution of thesintered particle group of hydroxyapatite (HAp) obtained in Example 2.

FIG. 8 is a chart representing results of x-ray diffraction performed onthe sintered particles of hydroxyapatite (HAp) obtained in Example 2 andComparative Example 1.

FIG. 9 is a chart representing results of FT-IR performed on thesintered particles of hydroxyapatite (HAp) obtained in Example 2 andComparative Example 1.

FIG. 10 is a graph representing a result of measurement, as measured bya dynamic light scattering method on particle size distribution of thesintered particle group of hydroxyapatite (HAp) obtained in a primaryparticle generating step of Example 3.

FIG. 11 is a graph representing a result of measurement, as measured bya dynamic light scattering method on particle size distribution of thesintered particle group of hydroxyapatite (HAp) obtained in ComparativeExample 2.

FIG. 12 is a graph representing a result of measurement, as measured bya dynamic light scattering method on particle size distribution of thesintered particle group of hydroxyapatite (HAp) obtained in Example 3.

FIG. 13 is a scanning electron micrograph (SEM) of the sintered particlegroup of rod-like hydroxyapatite (HAp) obtained in Example 3.

FIG. 14 is a graph representing a result of measurement, as measured bya dynamic light scattering method on particle size distribution of thesintered particle group of hydroxyapatite (HAp) obtained in a primaryparticle generating step of Example 4.

FIG. 15 is a graph representing a result of measurement, as measured bya dynamic light scattering method on particle size distribution of thesintered particle group of hydroxyapatite (HAp) obtained in Example 4.

FIG. 16 is a graph representing a result of measurement, as measured bya dynamic light scattering method on particle size distribution of thesintered particle group of hydroxyapatite (HAp) obtained in ComparativeExample 3.

FIG. 17 is a scanning electron micrograph (SEM) of the sintered particlegroup of rod-like (bar-like) hydroxyapatite (HAp) obtained in Example 4.

FIG. 18 is a scanning electron micrograph (SEM) of the sintered particlegroup of hydroxyapatite (HAp) obtained in Comparative Example 3.

FIG. 19 is a histogram representing specific surface areas of a primaryparticle group and sintered particle group of hydroxyapatite (HAp)obtained in Example 4, and a specific surface area of the sinteredparticle group of hydroxyapatite (HAp) obtained in Comparative Example3.

BEST MODE FOR CARRYING OUT THE INVENTION

The following will describe an embodiment of the present invention. Itshould be appreciated that the invention is not limited in any way bythe following description.

[Producing Method of a Ceramic Particle Group According to the PresentInvention]

The following will describe a method for producing a ceramic particlegroup according to the present invention.

A ceramic produced in the present invention is not particularly limitedas long as it is a solid material obtained by sintering (baking) asource material. The term “ceramic” is not just confined to the meaningof “ceramic” in general, but it also encompasses a broad range ofceramics such as “new ceramic” and “fine ceramic.” Examples of ceramicmaterials include alumina, zirconia, titania, titanium oxide, titaniumnitride, silica, graphite, magnetite, calcium carbonate, calciumsulfate, and calcium phosphate (including hydroxyapatite).

Among these examples, ceramics made from calcium phosphate (CaP), asrepresented by hydroxyapatite (HAp), are of great interest as bioactiveceramics (bio-ceramics), and this particular type of ceramic materialhas been suitably used in medical and other applications. This makescalcium phosphate suitable as a ceramic material for use in a producingmethod of a ceramic particle group according to the present invention.Specific examples of calcium phosphate (CaP) include hydroxyapatite(Ca₁₀(PO₄)₆(OH)₂), tricalcium phosphate (Ca₃(PO₄)₂), calciummetaphosphate (Ca(PO₃)₂), Ca₁₀(PO₄)₆F₂, and Ca₁₀(PO₄)₆Cl₂. Note that,the calcium phosphate (CaP) used in the present invention may beartificially synthesized by conventional methods such as a wet method, adry method, hydrolysis method, and hydrothermal method, or may beobtained from natural sources such as bones and teeth. Further, thecalcium phosphate (CaP) may include compounds in which some of thehydroxide ions and/or phosphate ions are replaced with carbonate ions,chloride ions, and/or fluoride ions.

A producing method of a ceramic particle group according to the presentinvention at least includes a mixing step and a sintering step, andoptionally includes a removing step and a primary particle generatingstep. The following describes a producing method that includes all ofthese four steps.

In a producing method of a ceramic particle group according to thepresent invention, these four steps are performed in the followingorder, for example:

1. Primary particle generating step

2. Mixing step

3. Sintering step

4. Removing step

1. Primary Particle Generating Step

As used herein, “primary particles” refers to particles of ceramicmaterial (calcium phosphate (CaP), hydroxyapatite (HAp), etc.) that areformed prior to sintering in the production of a ceramic particle group.In other words, the primary particles are the first particles formed inthe production of ceramic particles. Narrowly interpreted, the term alsomeans monocrystalline particles. Further, as the term is used herein,“primary particles” may be in an amorphous state, or a sintered stateafter the amorphous primary particles have been sintered.

In contrast, “secondary particles” refers to particles whose formationis due to physical bonding, such as fusion, or chemical bonding, such asionic bonding or covalent bonding, of primary particles. The number ofbonds binding the primary particles, or the shape of the bondedparticles is not particularly limited. The term “secondary particles”means any particles whose formation is due to bonding of two or moreprimary particles.

Further, “monocrystalline primary particles” means primary particles ofsingle crystal of ceramic material, or a cluster formed by ionicinteractions between primary particles of single crystal. As usedherein, an “cluster formed by ionic interactions between particles”means a cluster that is formed when the particles, dispersed in water ora medium containing an organic solvent, self-assembly by ionicinteractions, and it excludes polycrystalline secondary particles thatare formed by the fusion of sintered particles.

The primary particle generating step is not particularly limited as longas it is a step in which the primary particles are formed. This step issuitably selected according to the type of ceramic material used. Forexample, calcium phosphate (CaP) particles precipitate by droppingphosphoric acid into a calcium hydroxide slurry at ordinary temperature.

In a producing method of a ceramic particle group according to thepresent invention, a group of primary particles generated in the primaryparticle generating step is sintered without causing fusion or otherundesirable conditions, so as to produce a ceramic particle group. Theconsequence is that the state of primary particles (particle diameter,particle size distribution) generated in the primary particle generatingstep is directly reflected upon the final product ceramic particles.Thus, in the case where a ceramic particle group is to be produced thathas a nanometer size and uniform (narrow particle size distribution)particle diameter, the primary particle group generated in the primaryparticle generating step needs to have a nanometer size and uniform(narrow particle size distribution) particle diameter.

In this case, the primary particles have a particle diameter in a rangeof 10 nm to 500 nm, more preferably 20 nm to 450 nm, and most preferably25 nm to 400 nm. Further, the primary particles preferably have acoefficient of variation no greater than 20%, more preferably no greaterthan 18%, and most preferably no greater than 15%. A particle diameterand a coefficient of variation of the primary particles can becalculated by measuring particle diameters of at least 100 primaryparticles, either by a dynamic light scattering method or with use of anelectron microscope. With such a primary particle group, a ceramicparticle group can be produced that can be suitably used, for example,as a medical material or a filler for chromatography.

A coefficient of variation can be calculated according to the formula:standard deviation/mean particle diameter×100(%), and it represents avariation of particle diameters among the particles.

A method of generating a primary particle group with a nanometer sizeand uniform (narrow particle size distribution range) particle diameteris not particularly limited. For example, a method developed by theinventors of the present invention can be used (Japanese Laid-OpenPatent Publication No. 2002-137910). Specifically, a solution of calciumand a solution of phosphoric acid are dissolved and mixed in an emulsionphase of a detergent/water/oil system, and a reaction is allowed attemperatures at or above the cloud point of the detergent, with theresult that fine particles (primary particles) of hydroxyapatite aresynthesized. By varying the functional groups and the ratio ofhydrophilic group to hydrophobic group, the size of hydroxyapatite fineparticles can be controlled.

The following describes principles of producing the hydroxyapatite fineparticles. In the foregoing method in which a solution of calcium and asolution of phosphoric acid are dissolved and mixed in an emulsion phaseof a detergent/water/oil system to produce fine particles ofhydroxyapatite, hydroxyapatite cores grow in the micelles of thedetergent to form crystals. With the reaction temperature at or abovethe cloud point of the detergent, the thermodynamic stability of themicelles can be controlled. That is, by increasing the reactiontemperature at or above the cloud point of the detergent, the forceacting upon the detergent to form micelles can be weakened. As one canimagine, this will increase the driving force that promotes crystalgrowth of hydroxyapatite in the micelles but that has been restricted bythe force maintaining the micelles. As a result, the force maintainingthe micelles and preventing crystal growth can be overcome. The shape ofcrystals can be controlled by taking advantage of this mechanism.

Important factors involving formation of micelles by the detergent arethe functional groups (hydrophilic moieties) of the detergent, and aratio of hydrophilic group to hydrophobic group within the molecule.These factors determine stability of the micelles and the cloud point.Different types of detergents have different cloud points. Thus, bysuitably selecting a detergent, it is possible to change the functionalgroups, and the ratio of hydrophilic group to hydrophobic group. As aresult, the size of hydroxyapatite fine particles can be controlled.

The type of detergent used in the present method is not particularlylimited, and various types of conventional detergents, such as anionic,cationic, ampholytic, and non-ionic detergents, as disclosed in JapaneseLaid-Open Patent Publication No. 5-17111, can be used. Specific examplesof non-ionic detergents include: polyoxyethylene alkylether,polyoxyethylene allylether, polyoxyethylene alkylallylether, aderivative of oxyethylene, a block co-polymer of oxyethylene andoxypropylene, sorbitan fatty acid ester, polyoxyethylene sorbitan fattyacid ester, polyoxyethylene sorbitol fatty acid ester, glycerine fattyacid ester, polyoxyethylene fatty acid ester, polyoxyethylenealkylamine. Specific examples of cationic detergents include: quaternaryammonium salts such as stearylamine hydrochloride,lauryltrimethylammonium chloride, and alkylbenzene dimethylammoniumchloride. Specific examples of anionic ions include: higher alcoholsulfuric acid ester salts such as sodium lauryl alcohol sulfuric acidester, and sodium oleyl alcohol sulfuric acid ester; alkyl sulfates suchas sodium lauryl sulfate and ammonium lauryl sulfate; and alkylallylsulfonates such as sodium dodecylbenzenesulfonate and sodiumdodecylnaphthalenesulfonate. Specific examples of ampholytic detergentsinclude: alkyl betaine detergents, alkyl amide betaine detergents, andamine oxide detergents. These detergents are used either individually orin combinations of more than one kind. Considering cloud point andsolubility, pentaethyleneglycol dodecylether is preferably used.

As the oil phase used in the present method, the following solvents canbe used, for example: hydrocarbons such as toluene, xylene, hexane,dodecane, and cyclohexane; halogenated hydrocarbons such aschlorobenzene and chloroform; ethers such as diethylether; alcohols suchas butanol; and ketones such as methyl isobutyl ketone andcyclohexanone. One or more kinds of solvents, weakly soluble in waterand capable of dissolving the detergent are selected according to thetype of detergent used. Considering solubility in water and detergent,dodecane is particularly preferable. Conditions such as reactiontemperature, reaction time, and the amount of source material added aresuitable selected according to the composition of the primary particles.Preferably, the reaction temperature does not exceed the temperaturethat causes the solution to boil, since the reactant is the aqueoussolution in this reaction. Specifically, it is preferable that the upperlimit of reaction temperature do not exceed 90° C.

The primary particles generating step may optionally include a step ofwashing the primary particles with water, and a step of collecting theprimary particles by centrifugation or filtration.

2. Mixing Step

In the mixing step, the primary particles are mixed with an anti-fusingagent. By placing the anti-fusing agent between the primary particlesgenerated in the primary particle generating step, the primary particlescan be prevented from fusing together in the next sintering step. Asused herein, the mixture of the primary particles and the anti-fusingagent, obtained in the mixing step, is referred to as “mixed particles.”

The anti-fusing agent is not particularly limited as long as it canprevent the primary particles from fusing together. However, it ispreferable that the anti-fusing agent be non-volatile at a sinteringtemperature of the sintering step. By being non-volatile under sinteringtemperature conditions, the anti-fusing agent stays between the primaryparticles during the sintering step, ensuring that the primary particlesremain fused together. It should be noted however that the anti-fusingagent does not need to be 100% non-volatile at the sinteringtemperature, but needs to be volatile to the extent where at least 10%of the anti-fusing agent remains between the primary particles after thesintering step. Further, the anti-fusing agent may be chemicallydegradable by the action of heat, so that it can be burned away in thesintering step. That is, the anti-fusing agent does not need to stay asthe same substance (compound) before and after the sintering step, aslong as it remains after the sintering step.

It is preferable that the anti-fusing agent be a substance that issoluble in a solvent, an aqueous solvent in particular. With ananti-fusing agent soluble in a solvent, a ceramic particle group mixedwith it only needs to be suspended in an aqueous solvent such asdeionized water to remove the anti-fusing agent (for example, calciumcarbonate). To describe more specifically, the anti-fusing agent thatdissolves in an aqueous solvent does not require an organic solvent forthe removal. This makes it possible for the removing step to eliminateequipment used for the removal procedure, as well as the waste disposalprocess for the organic solvent. That is, the anti-fusing agent can beremoved from the ceramic particle group more easily. The type of solventis not particularly limited. Examples of the aqueous solvent includewater, ethanol, and methanol. As the organic solvent, acetone or toluenecan be used, for example.

In order to improve solubility of the anti-fusing agent in water, theaqueous solvent may include a chelate compound such as oxalate, ethylenediamine, bipyridine, or ethylene diamine tetraacetate. Further, in orderto improve solubility of the anti-fusing agent in water, the aqueoussolvent may include electrolytic ions such as sodium chloride, ammoniumnitrate, or potassium carbonate.

Here, the solubility of the anti-fusing agent in the solvent should beas high as possible since it increases the efficiency of removal. Thesolubility, as defined herein by the quantity in grams of solute thatdissolves in 100 g of solvent, is preferably no less than 0.01 g, morepreferably no less than 1 g, and most preferably no less than 10 g.

Specific examples of the anti-fusing agent include: calcium salts (or acomplex thereof), such as calcium chloride, calcium oxide, calciumsulfate, calcium nitrate, calcium carbonate, calcium hydroxide, calciumacetate, and calcium citrate; potassium salts such as potassiumchloride, potassium oxide, potassium sulfate, potassium nitrate,potassium carbonate, potassium hydroxide, and potassium phosphate; andsodium salts such as sodium chloride, sodium oxide, sodium sulfate,sodium nitrate, sodium carbonate, sodium hydroxide, and sodiumphosphate.

The method by which the primary particles are mixed with the anti-fusingagent in the mixing step is not particularly limited. For example, asolid mixture of primary particles and anti-fusing agent may be preparedfirst, which is then mixed together with a blender. Alternatively, theprimary particles may be dispersed in a solution of anti-fusing agent.However, since it is difficult to obtain a uniform mixture of solid, thelatter method is more preferable in order to uniformly and reliablyplace the anti-fusing agent between the primary particles. In using thelatter method, it is preferable to dry the anti-fusing agent solutiondispersing the primary particles. In this way, a uniform mixture ofprimary particles and anti-fusing agent can be kept for extended timeperiods. In Examples to be described later, 0.5 g of hydroxyapatite(HAp) primary particles were dispersed in a saturated aqueous solutionof calcium carbonate, and the mixture was dried at 80° C. to obtainmixed particles.

The mixing step may be a step in which the primary particles are mixedwith a solution containing a high-molecular compound having any of acarboxyl group, a sulfuric acid group, a sulfonic acid group, aphosphoric acid group, a phosphonic acid group, and an amino group onthe side chains, and in which metal salts (alkali metal salt and/oralkali earth metal salt and/or transition metal salt) are added to themixture. In this way, the high-molecular compound is adsorbed on thesurface of the hydroxyapatite (HAp) so that there will be no contactbetween molecules of hydroxyapatite (HAp) in the mixing procedure withthe anti-fusing agent. Further, by adding calcium salts, the anti-fusingagent always deposits on the surface of the hydroxyapatite (HAp). In thefollowing, a high-molecular compound having any of a carboxyl group, asulfuric acid group, a sulfonic acid group, a phosphoric acid group, aphosphonic acid group, and an amino group on the side chains will bereferred to simply as a “high-molecular compound.”

The high-molecular compound is not particularly limited as long as ithas any of a carboxyl group, a sulfuric acid group, a sulfonic acidgroup, a phosphoric acid group, a phosphonic acid group, and an aminogroup on the side chains. Examples of a high-molecular compound having acarboxyl group on the side chains include: poly(acrylic acid),poly(methacrylic acid), carboxymethyl cellulose, and a co-polymer ofstyrene and maleic anhydride. Examples of a high-molecular compoundhaving a sulfuric acid group on the side chain include: poly(acryloyloxyalkylsulfuric acid), poly(methacryloyloxy alkylsulfuric acid),poly(styrene sulfuric acid). Examples of a high-molecular compoundhaving a sulfonic acid group on the side chain include: poly(sufoalkylacrylate), poly(sufoalkyl methacrylate), and poly(styrene sulfonicacid). Examples of a high-molecular compound having a phosphoric acidgroup on the side chain include: poly(phosphoalkyl acrylate),poly(phosphoalkyl methacrylate), poly(styrene phosphoric acid), andpoly(acrylamido-N-methylphosphoric acid). Examples of a high-molecularcompound having a phosphonic acid group on the side chain include:poly(acryloyloxy alkylphosphonic acid), poly(methacryloyloxyalkylphosphonic acid), poly(styrene phosphonic acid),poly(acrylamido-N-methylphosphonic acid), and poly(vinyl alkylphosphonicacid). Examples of a high-molecular compound having an amino group onthe side chain include: polyacrylamide, poly(vinyl amine),poly(aminoalkyl methacrylate), polyamino styrene, a polypeptide, and aprotein. Different kinds of high-molecular compounds may be usedtogether in the mixing step, though one kind of high-molecular compoundis sufficient.

The molecular weight of the high-molecular compound is not particularlylimited. However, a molecular weight in a range of 100 g/mol to1,000,000 g/mol, inclusive, is preferable, 500 g/mol to 500,000 g/mol,inclusive, is more preferable, and 1,000 g/mol to 300,000 g/mol,inclusive, is most preferable. A molecular weight below these preferableranges reduces the proportion of the high-molecular compound caughtbetween the primary particles, with the result that the primaryparticles contact more frequently. A molecular weight above thesepreferable ranges results in poor operability, because it reduces thesolubility of the high-molecular compound and increases the viscosity ofthe solution containing the high-molecular compound, among other things.

The solution containing the high-molecular compound is preferably anaqueous solution. This is because sintered particles of hydroxyapatite(HAp) dissolve under strong acidic conditions. The pH of aqueoussolution containing the high-molecular compound is not particularlylimited as long as it falls in a range of 5 to 14, inclusive, and doesnot dissolve the HAp particles. Such an aqueous solution containing thehigh-molecular compound is prepared by dissolving the high-molecularcompound in distilled water, ion-exchange water or the like, andadjusting the pH with aqueous ammonia, or an aqueous solution of sodiumhydroxide or potassium hydroxide.

The concentration of the high-molecular compound contained in theaqueous solution is preferably in a range of 0.001% w/v to 50% w/v, morepreferably 0.005% w/v to 30% w/v, and most preferably 0.01% w/v to 10%w/v, inclusive. A concentration below these preferable ranges is notpreferable because, in this case, only a small quantity ofhigh-molecular compound is placed between the primary particles, withthe result that the primary particles contact more frequently. Aconcentration above these preferable ranges results in poor operabilitybecause it makes it difficult to dissolve the high-molecular compoundand increases the viscosity of the solution containing thehigh-molecular compound, among other things.

In the mixing step of the present invention, the solution containing thehigh-molecular compound is mixed with the primary particles. This isattained by placing the primary particles in the solution and dispersingthe primary particles therein, for example, by agitating. In a producingmethod of a ceramic particle group according to the present invention,this causes the high-molecular compound to be adsorbed on the surface ofthe primary particles, with the result that any of the carboxyl group,sulfuric acid group, sulfonic acid group, phosphoric acid group,phosphonic acid group, and amino group is attached to the surface of theprimary particles. In the solution, the carboxyl group, sulfuric acidgroup, sulfonic acid group, phosphoric acid group, phosphonic acidgroup, or amino group exists as ions.

Next, the mixture of the primary particles and the solution containingthe high-molecular compound is supplemented with metal salts (alkalimetal salts and/or alkali earth metal salts and/or transition metalsalts). This causes the metal ions (alkali metal ions and/or alkaliearth metal ions and/or transition metal ions) to bind to thecarboxylate ion, sulfate ion, sulfonate ion, phosphate ion, phosphonateion, or amino ion that is present on the surface of the primaryparticles, with the result that carboxylate, sulfate, sulfonate,phosphate, phosphonate, or an amino acid salt is generated on thesurface of the primary particles. The carboxylate, sulfate, sulfonate,phosphate, phosphonate, or an amino acid salt of the metals (alkalimetal and/or alkali earth metal and/or transition metal) serve as theanti-fusing agent. That is, the primary particles with the carboxylate,sulfate, sulfonate, phosphate, phosphonate, or an amino acid salt of themetals (alkali metal and/or alkali earth metal and/or transition metal)are “mixed particles.” The carboxylate, sulfate, sulfonate, phosphate,phosphonate, or an amino acid salt of the metals (alkali metal and/oralkali earth metal and/or transition metal) precipitate. Theprecipitates are collected and dried to be used in the sintering step.For example, the precipitates can be dried by the action of heat(preferably 0° C. to 200° C., more preferably 20° C. to 150° C., andmost preferably 40° C. to 120° C., inclusive) under reduced pressureconditions, for example (preferably 1×10⁵ Pa to 1×10⁻⁵ Pa, morepreferably 1×10³ Pa to 1×10⁻³ Pa, and most preferably 1×10² Pa to 1×10⁻²Pa, inclusive). The precipitates are preferably dried under reducedpressure because it can lower the drying temperature; however, theprecipitates may be dried under atmospheric pressure as well.

The alkali metal salts are not particularly limited. For example, thefollowing compounds can be used: sodium chloride, sodium hypochlorite,sodium chlorite, sodium bromide, sodium iodide, sodium folate, sodiumoxide, sodium peroxide, sodium sulfate, sodium thiosulfate, sodiumselenate, sodium nitrite, sodium nitrate, sodium phosphide, sodiumcarbonate, sodium hydroxide, potassium chloride, potassium hypochlorite,potassium chlorite, potassium bromide, potassium iodide, potassiumfolate, potassium oxide, potassium peroxide, potassium sulfate,potassium thiosulfate, potassium selenate, potassium nitrite, potassiumnitrate, potassium phosphide, potassium carbonate, and potassiumhydroxide.

The alkali earth metal salts may be, for example, magnesium chloride,magnesium hypochlorite, magnesium chlorite, magnesium bromide, magnesiumiodide, magnesium folate, magnesium oxide, magnesium peroxide, magnesiumsulfate, magnesium thiosulfate, magnesium selenate, magnesium nitrite,magnesium nitrate, magnesium phosphide, magnesium carbonate, magnesiumhydroxide, calcium chloride, calcium hypochlorite, calcium chlorite,calcium bromide, calcium iodide, calcium folate, calcium oxide, calciumperoxide, calcium sulfate, calcium thiosulfate, calcium selenate,calcium nitrite, calcium nitrate, calcium phosphide, calcium carbonate,or calcium hydroxide.

The transition metal salts may be, for example, zinc chloride, zinchypochlorite, zinc chlorite, zinc bromide, zinc iodide, zinc folate,zinc oxide, zinc peroxide, zinc sulfate, zinc thiosulfate, zincselenate, zinc nitrite, zinc nitrate, zinc phosphide, zinc carbonate,zinc hydroxide, iron chloride, iron hypochlorite, iron chlorite, ironbromide, iron iodide, iron folate, iron oxide, iron peroxide, ironsulfate, iron thiosulfate, iron selenate, iron nitride, iron nitrate,iron phosphide, iron carbonate, or iron hydroxide. Nickel compounds maybe used as well.

The metal salts (alkali metal salt, alkali earth metal salt, transitionmetal salt) added to the mixture of the primary particles and thesolution containing the high-molecular compound may be of one kind or amixture of more than one kind. Further, the metal salts (alkali metalsalt, alkali earth metal salt, transition metal) may be solid, or morepreferably an aqueous solution, because it allows the metal salts to beuniformly added and allows the concentration to be controlled, amongother things. The quantity (concentration) of the metal salts (alkalimetal salt and/or alkali earth metal salt and/or transition metal salt)is suitably determined and is not particularly limited as long as itallows the metal slats to bind to the carboxylate ion, sulfate ion,sulfonate ion, phosphate ion, phosphonate ion, or amino ion on thesurface of the primary particles, and form carboxylate, sulfate,sulfonate, phosphate, phosphonate, or an amino acid salt of the metals(alkali metal and/or alkali earth metal and/or transition metal).

The carboxylate, sulfate, sulfonate, phosphate, phosphonate, or an aminoacid salt of the metals formed on the surface of the primary particlesin this step are thermally decomposed into oxides of the metals (alkalimetal and/or alkali earth metal and/or transition metal) in thesintering step. For example, in the case where calcium polyacrylate isformed on the surface of the primary particles, calcium polyacrylatedecomposes into calcium oxide in the sintering step. The metal oxides(alkali metal oxide and/or alkali earth metal oxide (for example,calcium oxide) and/or transition metal oxide) are water soluble, andtherefore can easily be removed in the removing step.

Note that, sodium polyacrylate is water soluble, and as such it candirectly be used as an anti-fusing agent in the mixing step. However,since calcium polyacrylate is insoluble in water, it is preferable thatcalcium salts be added after polyacrylic acid alone has been adsorbed onthe surface of the primary particles, so as to allow calciumpolyacrylate to deposit on the surface of the primary particles.Further, since the high-molecular compound is decomposed when theprimary particles are pre-baked at high temperatures (about 300° C. orabove), it is preferable to deposit the metal salts of thehigh-molecular compound on the surface of the primary particles, so thatthe high-molecular compound can remain as the anti-fusing agent evenafter pre-baking. However, when the primary particles are pre-baked(heat treatment) at temperatures that do not decompose (soften) thehigh-molecular compound, it is not necessarily required to deposit themetal salts of the high-molecular compound on the surface of the primaryparticles.

3. Sintering Step

The sintering step is a step in which the mixed particles obtained inthe mixing step is treated under sintering temperatures to produceceramic particles (sintered particles) from the primary particlescontained in the mixed particles. By the presence of the anti-fusingagent between the primary particles, the primary particles do not fusetogether even at the high temperatures of the sintering step.

The sintering temperature in the sintering step is suitably setaccording to the intended hardness of the ceramic particles. Forexample, a range of 100° C. to 1800° C. is preferable, 150° C. to 1500°C. is more preferable, and 200° C. to 1200° C. is most preferable. Thesintering time is suitably set according to the intended hardness orother conditions of the ceramic particles. In the Examples describedbelow, sintering is performed for 1 hour at 800° C.

The apparatuses or other equipment used in the sintering step are notparticularly limited and are suitably selected from commerciallyavailable sintering furnaces according to the scale of manufacture,manufacturing conditions, etc.

Removing Step

The removing step is a step in which the anti-fusing agent betweenparticles of the ceramic particle group obtained in the sintering stepis removed.

The procedures and methods of removal are suitably selected according tothe type of anti-fusing agent used in the mixing step. For example, inthe case where the anti-fusing agent is solvent soluble, only theanti-fusing agent is dissolved and removed with the use of a solventthat does not dissolve the ceramic particles but dissolves theanti-fusing agent. The type of solvent is not particularly limited andmay be an aqueous solvent or an organic solvent, as long as it satisfiesthe foregoing conditions. Examples of an aqueous solvent include water,ethanol, and methanol. Examples of organic solvent include acetone andtoluene.

In order to improve solubility of the anti-fusing agent in water, theaqueous solvent may include a chelate compound such as oxalate, ethylenediamine, bipyridine, or ethylene diamine tetraacetate. Further, in orderto improve solubility of the anti-fusing agent in water, the aqueoussolvent may include electrolytic ions such as sodium chloride, ammoniumnitrate, or potassium carbonate.

The aqueous solvent is more preferable over organic solvent because itdoes not require equipment necessary for the organic solvent, nor doesit require any waste disposal procedures. Other advantages of aqueoussolvent include safety in manufacture, and small environmental risks.

In the case of hydroxyapatite (HAp) sintered particles, the removingstep is preferably performed in a pH range of 4.0 to 12.0, because thehydroxyapatite (HAp) sintered particles dissolve below pH 4.0.

In the case of removing the anti-fusing agent using a solvent, theceramic particle group containing the anti-fusing agent, obtained in thesintering step, is first suspended in a solvent, and this is followed byfiltration or centrifugation to collect only the ceramic particles. In aproducing method of a ceramic particle group according to the presentinvention, the foregoing procedures may be performed more than once. Byrepeating the procedures, the anti-fusing agent between the ceramicparticles can be removed more effectively. However, the proceduresshould not be repeated more than necessary, since doing so complicatesthe manufacturing steps, increases manufacturing costs, and lowers therate of collecting the ceramic particles, among other things. As such,the number of times the foregoing procedures are repeated is suitablydecided according to the desired removal rate of the anti-fusing agent.

Note that, the removing step may optionally include a step ofclassifying the particles into a uniform particle diameter.

Instead of using a solvent, the anti-fusing agent can be removed withuse of a magnet, by using a magnetic material for the anti-fusing agent.Specifically, the ceramic particle group (crude ceramic particle) groupcontaining the anti-fusing agent, obtained in the sintering step, issuspended and dispersed in a suitable solvent (for example, water), and,under the magnetic force acting on the suspension, only the anti-fusingagent is attracted to the magnet and the ceramic particles, notattracted to the magnet, are collected. Alternatively, instead ofsuspending in a solvent, the crude ceramic particles may be ground intoa powder, and the anti-fusing agent may be separated with a magnet.However, the anti-fusing agent can be removed more efficiently in asuspension, because it readily allows the anti-fusing agent to bedetached from the ceramic particles. In using these methods, the ceramicparticles should preferably be non-magnetic or weakly magnetic.

[Ceramic Particle Group According to the Present Invention]

In a ceramic particle group produced by a producing method of a ceramicparticle group according to the present invention (hereinafter, referredto as “ceramic particle group according to the present invention”), theanti-fusing agent prevents the primary particles from fusing together.As such, the majority of the ceramic particles retain the state ofprimary particles. Thus, when suspended in a solvent, the majority ofthe ceramic particle group is dispersed as primary particles of singlecrystal, or a cluster of primary particles of single crystal that areheld together by ionic interactions (monocrystalline primary particles).

As described above, in order to adsorb the ceramic particle group on ahigh-molecular medical substrate, it is important that the ceramicparticle group be highly dispersive. For use as a chromatography filler,it is important that the ceramic particle group have a large surfacearea. In a ceramic particle group according to the present invention,the majority of the particles exist as primary particles of singlecrystal, or a cluster of primary particles of single crystal that areheld together by ionic interactions (monocrystalline primary particles).As such, a ceramic particle group according to the present invention ishighly dispersive, and, owning to the fact that it does not formsecondary particles, a ceramic particle group according to the presentinvention has a large surface area. This makes a ceramic particle groupaccording to the present invention suitable for the foregoingapplication.

In order to evaluate whether the ceramic particles exist as primaryparticles, the following methods can be used for example. In one method,a result of measurement on particle diameter by electron microscopy iscompared with that measured in a suspension by a dynamic lightscattering method. If the results match, most of the particles in theceramic particle group can be regarded as the primary particles. If thelatter is greater than the former, the ceramic particles can be regardedas the secondary particles formed by the primary particles fusedtogether.

The solvent in which the ceramic particle group is dispersed is notparticularly limited as long as it does not dissolve the ceramicparticles. Water is one example. Other examples include: alcohols suchas methanol and ethanol; ketones such as acetone, methylethyl ketone,methylisobutyl ketone, and cyclohexanone; amides such asN,N-dimethylformamide; sulfoxides such as dimethylsulfoxide;hydrocarbons such as toluene, xylene, hexane, dodecane, and cyclohexane;halogenated hydrocarbons such as chlorobenzene and chloroform; andethers such as diethyl ether and dioxane. These solvents may be usedeither individually or in a combination of more than one kind, dependingon intended use.

From a particle diameter distribution determined by the dynamic lightscattering method, one can calculate a proportion of particles whoseparticle diameters match the particle diameters of the primary particlesas determined by electron microscopy. In this way, it is possible toobtain a proportion of primary particles of single crystal, or aproportion of a cluster of primary particles of single crystal that areheld together by ionic interactions (monocrystalline primary particles).

According to a producing method of a ceramic particle group according tothe present invention, at least 50% of the ceramic particles exist asprimary particles of single crystal, a 60% or greater proportion of theceramic particles exist as primary particles of single crystal underdesirable conditions, and a 70% or greater proportion of the ceramicparticles exist as primary particles of single crystal under optimumconditions, though the proportions vary depending on conditions such asthe source material used, the type of anti-fusing agent, and sinteringconditions.

When the ceramic particles are adsorbed in a high-molecular medicalsubstrate, or when the ceramic particles are used as chromatographyfillers, medical materials, and the like, it is preferable that theceramic particles be nanometer size particles. Such a nanometer sizeceramic particle group can be produced by producing nanometer sizeprimary particles in the primary particles generating step in aproducing method of a ceramic particle group according to the presentinvention. When the primary particles produced in the primary particleproducing step in a producing method according to the present inventionhave a particle diameter in a range of 10 nm to 500 nm, more preferably20 nm to 450 nm, or most preferably 25 nm to 400 nm, it is possible toproduce a ceramic particle group with a particle diameter that falls ina range of 10 nm to 700 nm, more preferably 20 nm to 600 nm, and mostpreferably 25 nm to 500 nm. In the Examples described below, theinventors of the present invention produced a sintered particle group ofhydroxyapatite (HAp) with a particle diameter of 30 nm to 100 nm, usinga producing method of a ceramic particle group according to the presentinvention.

Further, it is preferable that a ceramic particle group has a uniformparticle diameter (narrow particle size distribution). Such a ceramicparticle group with a uniform particle diameter (narrow particle sizedistribution) can be produced by producing a primary particle group witha uniform particle diameter (narrow particle size distribution) in theprimary particle generating step in a producing method of a ceramicparticle group according to the present invention. When the particlediameter of a primary particle group in the primary particles producedin the primary particle generating step of a producing method accordingto the present invention has a coefficient of variation at or below 20%,more preferably at or below 18%, and most preferably at or below 15%, itis possible to produce a ceramic particle group whose particle diameterhas a coefficient of variation at or below 20%, more preferably at orbelow 18%, and most preferably at or below 15%. In the Examplesdescribed below, the inventors of the present invention produced asintered particle group of hydroxyapatite (HAp) whose particle diameterhad a coefficient of variation at or below 12%, using a producing methodof a ceramic particle group according to the present invention. Such aceramic particle group with a uniform particle diameter (narrow particlesize distribution) can be suitably used, for example, when it isadsorbed on a high-molecular medical substrate, or when it is used forchromatography fillers, medical materials, and the like.

As described in the BACKGROUND ART section, it has been physicallydifficult to realize a nanometer size ceramic particle group with auniform particle diameter (narrow particle size distribution). Thepresent invention realizes a nanometer size ceramic particle group witha uniform particle diameter (narrow particle size distribution), withoutrequiring sophisticated classification procedures. This greatly enhancesthe applicability of the ceramic.

[Use of a Ceramic Particle Group According to the Present Invention]

A ceramic particle group according to the present invention, and asintered particle group of calcium phosphate (CaP) as represented byhydroxyapatite (HAp) in particular, have very strong bio-activities.This enhances their applicability in medicine, for example, as dental ormedical materials such as bone fillers, dental fillers, and drugreleasing agents. Calcium phosphates (CaP) such as hydroxyapatite (HAp)are particularly suitable as medical materials due to their strongbio-activity. A sintered particle group of calcium phosphate (CaP) canbe suitably used as a support for immobilizing bacteria or yeasts, aswell as a column chromatography filler, or an adsorbent such as adeodorizer. A particle group of calcium phosphate (CaP) clusters is alsopotentially applicable to a nanometer size drug delivery system (nanoDDS).

For example, when a sintered particle group of calcium phosphate (CaP)according to the present invention is used as a column chromatographyfiller, the resolution of analysis can be improved due to the uniformparticle diameter (narrow, particle size distribution). Further, when asintered particle group of calcium phosphate (CaP) according to thepresent invention is used as a medical material such as a drug releasingagent, the amount of drug released per unit time can be controlled moreaccurately due to the narrow particle size distribution of the particlegroup. Further, since a sintered particle group of calcium phosphate(CaP) according to the present invention excels in keeping moisture andabsorbing skin oil, it can be used as a cosmetic additive. Further, asintered particle group of calcium phosphate (CaP) according to thepresent invention can easily blend into other substances or materials.By combining this property with the superior biocompatibility andenvironmental friendliness, a sintered particle group of calciumphosphate (CaP) according to the present invention can be used as analternative material of asbestos, which have been used as buildingmaterials such as a wall material, a roof material, an exteriormaterial, and an interior material. Other than building materials, asintered particle group of calcium phosphate (CaP) according to thepresent invention is applicable to various industrial materials, forexample, such as a joint sheet, a sealant, a heat-resistant material,brakes (wearing material), a fibrous material for antifriction, anadhesive, and a filler for paint.

The following will describe an embodiment of the present invention basedon attached drawings and Examples. The present invention is not limitedto the description of the Examples below, but may be altered by askilled person within the scope of the claims. An embodiment based on aproper combination of technical means disclosed in different embodimentsis encompassed in the technical scope of the present invention.

EXAMPLES

The following Examples describe examples of producing a sinteredparticle group of hydroxyapatite (HAp). The present invention is notlimited in any way by the description of the following Examples.

Example 1

(Primary Particle Generating Step)

As a continuous oil phase, dodecane [CH₃(CH₂)₁₀CH₃] was used. As anon-ionic detergent, pentaethylene glycol dodecylether[CH₃(CH₂)₁₀CH₂O(CH₂CH₂O)₄CH₂CH₂OH] with the cloud point of 31° C. wasused. At room temperature, 40 ml of continuous oil phase containing 0.5g of the non-ionic detergent was prepared. Then, 10 ml of 2.5 mol/lcalcium hydroxide [Ca(OH)₂]-dispersed aqueous solution was added to thecontinuous oil phase to prepare a water-in-oil solution (W/O solution).Then, 10 ml of 1.5 mol/l potassium dihydrogen phosphate [(KH₂PO₄)]solution was added to the W/O solution with agitation. The mixture wasstirred for 24 hours at room temperature to promote reaction.

The product of reaction was separated and washed by centrifugation toobtain primary particles of hydroxyapatite (HAp). The primary particlesin a primary particle group of hydroxyapatite (HAp) had a particlediameter of 30 nm to 100 nm. A coefficient of variation of the particlediameter was no greater than 11%.

(Mixing Step)

As an anti-fusing agent, CaCO₃ was used. To a CaCO₃ saturated solutioncontaining 0.1 g of CaCO₃, 0.5 g of primary particle group ofhydroxyapatite (HAp) was dispersed. The solution was dried at 80° C. toobtain mixed particles.

(Sintering Step)

The mixed solution was placed in a crucible and was sintered at 800° C.for 1 hour.

(Removing Step)

The sintered particles were suspended in distilled water. By removingthe anti-fusing agent by centrifugation, a sintered particle group ofhydroxyapatite (HAp) was collected. The sintered particles ofhydroxyapatite (HAp) were type B carbonate apatite and had strongbio-activity. Element analysis found that Ca/P ratio was 1.58,confirming that the sintered particles of hydroxyapatite (HAp) was acalcium-deficient apatite.

Comparative Example 1

For comparison, 0.5 g of primary particles of hydroxyapatite (HAp)obtained in the primary particle generating step of Example 1 wereplaced in a crucible, and were sintered for 1 hour at 800° C. to obtaina sintered particle group of hydroxyapatite (HAp). That is, in thisexample, a sintered particle group of hydroxyapatite (HAp) was producedwithout the anti-fusing agent CaCO₃.

Comparison between Example 1 and Comparative Example 1

FIG. 1 represents a scanning electron micrograph (SEM) of the sinteredparticle group of hydroxyapatite (HAp) obtained in Example 1. FIG. 2represents a SEM of a sintered particle group of hydroxyapatite (HAp)obtained in Comparative Example 1. It was found from the results of SEMthat these sintered particle groups of hydroxyapatite (HAp) had particlediameters of about 30 nm to about 100 nm. As the scanning electronmicroscope, JSM-6301F of JEOL was used. Observation was made at ×90,000.

The sintered particle groups of hydroxyapatite (HAp) were dispersed inethanol and particle size distributions (distributions of particlediameters) were measured by a dynamic light scattering method. FIG. 3(a) shows the result for the sintered particle group of hydroxyapatite(HAp) obtained in Example 1, and FIG. 3( b) shows the result for thesintered particle group of hydroxyapatite (HAp) obtained in ComparativeExample 1. For the measurement of dynamic light scattering, the dynamiclight scattering photometer DLS-6000 of Otsuka Electronics Co., Ltd. wasused. The measurement was performed at room temperature, a 10 ppmparticle concentration, and a scattering angle of 90°.

It can be seen from the result shown in FIG. 3( a) that the sinteredparticle group of hydroxyapatite (HAp) obtained in Example 1 had aparticle diameter of about 70 nm to about 120 nm. This substantiallymatched the particle diameter observed by SEM.

It was therefore confirmed that the sintered particle group ofhydroxyapatite (HAp) obtained in Example 1 was dispersed in ethanol inthe form of primary particles of single crystal. Almost all of thesintered particles, 96% to be exact, existed as primary particles. Acoefficient of variation of particle diameter was 12%, showing that theparticle group of hydroxyapatite (HAp) had a uniform particle diameter(narrow particle size distribution).

From the result shown in FIG. 3( b), the sintered particle group ofhydroxyapatite (HAp) obtained in Comparative Example 1 had a particlediameter of about 600 nm to about 3000 nm. This was inconsistent withthe result of SEM. A coefficient of variation of particle diameter was57%, much greater than that of Example 1. This suggests that thesintered particle group of hydroxyapatite (HAp) obtained in ComparativeExample 1 has formed secondary particles, with the primary particlesrandomly fused together.

FIG. 4 shows the results of x-ray diffraction for the sintered particlesof hydroxyapatite (HAp) obtained in Example 1 and Comparative Example 1.FIG. 5 shows the results of FT-IR for the sintered particles ofhydroxyapatite (HAp) obtained in Example 1 and Comparative Example 1. InFIG. 4 and FIG. 5, the results for Example 1 and Comparative Example 1are indicated by solid line and broken line, respectively. It was foundfrom the results shown in FIGS. 4 and 5 that the sintered particles ofhydroxyapatite (HAp) obtained in Example 1 and Comparative Example 1were both calcium phosphate (hydroxyapatite (HAp)).

The foregoing results revealed that the sintered particle group ofhydroxyapatite (HAp) obtained in Example 1 was highly dispersive, withalmost all (96%) of the particles dispersed as primary particles ofsingle crystal when suspended in a solvent, and that the sinteredparticle group of hydroxyapatite (HAp) obtained in Example 1 had ananometer size particle diameter of about 70 nm to about 120 nm, whichwere more uniform (narrow particle size distribution) compared with thatof Comparative Example 1.

Example 2

(Primary Particle Generating Step)

As a continuous oil phase, dodecane [CH₃(CH₂)₁₀CH₃] was used. As anon-ionic detergent, pentaethylene glycol dodecylether[CH₃(CH₂)₁₀CH₂O(CH₂CH₂O)₄CH₂CH₂OH] with the cloud point of 31° C. wasused. At room temperature, 40 ml of continuous oil phase containing 0.5g of the non-ionic detergent was prepared. Then, 10 ml of 2.5 mol/lcalcium hydroxide [Ca(OH)₂]-dispersed aqueous solution was added to thecontinuous oil phase to prepare a water-in-oil solution (W/O solution).Then, 10 ml of 1.5 mol/l potassium dihydrogen phosphate [(KH₂PO₄)]solution was added to the W/O solution with agitation. The mixture wasstirred for 24 hours at room temperature to promote reaction.

The product of reaction was separated and washed by centrifugation toobtain primary particles of hydroxyapatite (HAp). The primary particlegroups of hydroxyapatite (HAp) were dispersed in ethanol and particlesize distributions (distributions of particle diameters) were measuredby a dynamic light scattering method. FIG. 6 shows the result. For themeasurement of dynamic light scattering, the dynamic light scatteringphotometer DLS-6000 of Otsuka Electronics Co., Ltd. was used. Themeasurement was performed at room temperature, a 10 ppm particleconcentration, and a scattering angle of 90°. According to the resultshown in FIG. 6, 95% of the primary particle group of hydroxyapatite(HAp) had a particle diameter in a range of 50 nm to 100 nm. Acoefficient of variation of the particle diameter was 15%.

(Mixing Step)

In a 100 ml aqueous solution (pH 12) containing 1.0 g of polyacrylicacid (the product of ALDRICH, weight-average molecular weight 15,000g/mol), 1.0 g of a primary particle group of hydroxyapatite (HAp) wasdispersed to adsorb polyacrylic acid on the surface of the particles.The 100 ml aqueous solution (pH 12) containing 1.0 g of polyacrylic acid(the product of ALDRICH, weight-average molecular weight 15,000 g/mol)was prepared as follows. First, 1.0 g of polyacrylic acid (the productof ALDRICH, weight-average molecular weight 15,000 g/mol) was dissolvedin 100 ml of deionized water. This was followed by addition of aqueousammonia (25% aqueous solution) at room temperature with stirring, so asto adjust pH of the polyacrylic acid aqueous solution at 12.0. The pH ofthe aqueous solution was measured with the pH meter D-24SE of HORIBALTD.

Next, 100 ml of 0.12 ml/l calcium nitrate [Ca(NO₃)₂] aqueous solutionwas added to the dispersion so prepared, so as to deposit calciumpolyacrylate on the surface of the primary particles. Here, calciumpolyacrylate serves as the anti-fusing agent. The resulting precipitateswere collected and were dried under reduced pressure (about 0.1 Pa) at80° C., so as to obtain mixed particles.

(Sintering Step)

The mixed particles were placed in a crucible and sintered therein for 1hour at 800° C. The heat decomposed calcium polyacrylate into calciumoxide [CaO]. After the sintering step, a 25% or greater proportion ofcalcium oxide [CaO] remained.

(Removing Step)

In order to more easily dissolve the anti-fusing agent in water, anaqueous solution of 50 mmol/l ammonium nitrate [NH₄NO₃] was prepared.The sintered particles were suspended in 500 ml of the aqueous solutionso prepared. This was followed by separation and washing bycentrifugation. The particles were further suspended in distilled water,and separated and washed again by centrifugation to remove theanti-fusing agent and ammonium nitrate and collect a sintered particlegroup of hydroxyapatite (HAp).

Comparison between Example 2 and Comparative Example 1

The sintered particle group of hydroxyapatite (HAp) obtained in Example2 was dispersed in ethanol and particle size distributions(distributions of particle diameters) were measured by a dynamic lightscattering method. FIG. 7 shows the result.

It can be seen from the result shown in FIG. 7 that 90% of particles inthe sintered particle group of hydroxyapatite (HAp) obtained in Example2 had a particle diameter in a range of 60 nm to 100 nm. Thissubstantially matched the particle diameter distributions of the primaryparticle group of hydroxyapatite (HAp) obtained in Example 2. Acoefficient of variation of particle diameter was 11%, showing that thesintered particle group of hydroxyapatite (HAp) had a uniform particlediameter (narrow particle diameter distribution).

From the result shown in FIG. 3( b), the sintered particle group ofhydroxyapatite (HAp) obtained in Comparative Example 1 had a particlediameter of about 600 nm to about 3000 nm. This suggests that thesintered particle group of hydroxyapatite (HAp) obtained in ComparativeExample 1 has formed secondary particles, with the primary particlesrandomly fused together. A coefficient of variation of particle diameterwas 57%, much greater than that of Example 2.

FIG. 8 shows the results of x-ray diffraction for the sintered particlesof hydroxyapatite (HAp) obtained in Example 2 and Comparative Example 1.FIG. 9 shows the results of FT-IR for the sintered particles ofhydroxyapatite (HAp) obtained in Example 2 and Comparative Example 1. InFIG. 8 and FIG. 9, the results for Example 2 and Comparative Example 1are indicated by broken line (upper line) and solid line (lower line),respectively. It was found from the results shown in FIGS. 8 and 9 thatthe sintered particles of hydroxyapatite (HAp) obtained in Example 2 andComparative Example 1 were both calcium phosphate (hydroxyapatite(HAp)).

The foregoing results revealed that the sintered particle group ofhydroxyapatite (HAp) obtained in Example 2 was highly dispersive, withalmost all (90%) of the particles dispersed as primary particles ofsingle crystal when suspended in a solvent, and that the sinteredparticle group of hydroxyapatite (HAp) obtained in Example 2 had ananometer size particle diameter of about 60 nm to about 100 nm, whichwere even more uniform (narrow particle size distribution) compared withthat of Example 1.

Example 3

(Primary Particle Generating Step)

As a continuous oil phase, dodecane [CH₃(CH₂)₁₀CH₃] was used. As anon-ionic detergent, pentaethylene glycol dodecylether[CH₃(CH₂)₁₀CH₂O(CH₂CH₂O)₄CH₂CH₂OH] with the cloud point of 31° C. wasused. At room temperature, 40 ml of continuous oil phase containing 0.5g of the non-ionic detergent was prepared. Then, at 95° C., 10 ml of 2.5mol/l calcium hydroxide [Ca(OH)₂]-dispersed aqueous solution was addedto the continuous oil phase to prepare a water-in-oil solution (W/Osolution). Then, 10 ml of 1.5 mol/l potassium dihydrogen phosphate[KH₂PO₄] aqueous solution was added to the W/O solution with agitation.The mixture was stirred for 24 hours at 95° C. to promote reaction.

The product of reaction was separated and washed by centrifugation toobtain primary particles of hydroxyapatite (HAp). The primary particlegroups of hydroxyapatite (HAp) were dispersed in ethanol and particlesize distributions (distributions of particle diameters) were measuredby a dynamic light scattering method. FIG. 10 shows the result. For themeasurement of dynamic light scattering, the dynamic light scatteringphotometer DLS-6000 of Otsuka Electronics Co., Ltd. was used. Themeasurement was performed at room temperature, a 10 ppm particleconcentration, and a scattering angle of 90°. According to the resultshown in FIG. 10, 89% of the primary particle group of hydroxyapatite(HAp) had a particle diameter in a range of 150 nm to 230 nm. Acoefficient of variation of the particle diameter was 14%.

(Mixing Step)

In a 100 ml aqueous solution (pH 7) containing 0.5 g of polyacrylic acid(the product of ALDRICH, weight-average molecular weight 15,000 g/mol),0.5 g of a primary particle group of hydroxyapatite (HAp) was dispersedto adsorb polyacrylic acid on the surface of the particles.

Next, 500 ml of saturated aqueous solution of calcium hydroxide[Ca(OH)₂] was added to the dispersion so prepared, so as to depositcalcium polyacrylate on the surface of the particles. Here, calciumpolyacrylate serves as the anti-fusing agent. The resulting precipitateswere collected and were dried under reduced pressure at 80° C., so as toobtain mixed particles.

(Sintering Step)

The mixed particles were placed in a crucible and sintered therein for 1hour at 800° C. The heat decomposed calcium polyacrylate into calciumoxide [CaO]. After the sintering step, a 50% or greater proportion ofcalcium oxide [CaO] remained.

(Removing Step)

In order to more easily dissolve the anti-fusing agent in water, anaqueous solution of 50 mmol/l ammonium nitrate [NH₄NO₃] was prepared.The sintered particles were suspended in 500 ml of the aqueous solutionso prepared. This was followed by separation and washing bycentrifugation. The particles were further suspended in distilled water,and separated and washed again by centrifugation to remove theanti-fusing agent and ammonium nitrate and collect a sintered particlegroup of hydroxyapatite (HAp).

Comparative Example 2

For comparison, 0.5 g of primary particle group of hydroxyapatite (HAp)obtained in the primary particle generating step of Example 3 wereplaced in a crucible, and were sintered for 1 hour at 800° C. to obtaina sintered particle group of hydroxyapatite (HAp). That is, in thisexample, a sintered particle group of hydroxyapatite (HAp) was producedwithout calcium polyacrylate used as the anti-fusing agent in Example 3.

Comparison between Example 3 and Comparative Example 2

The sintered particle groups of hydroxyapatite (HAp) were dispersed inethanol and particle size distributions (distributions of particlediameters) were measured by a dynamic light scattering method. FIG. 12shows the result for the sintered particle group of hydroxyapatite (HAp)obtained in Example 3, and FIG. 11 shows the result for the sinteredparticle group of hydroxyapatite (HAp) obtained in Comparative Example2.

It can be seen from the result shown in FIG. 12 that 92% of particles inthe sintered particle group of hydroxyapatite (HAp) obtained in Example3 had a particle diameter in a range of 150 nm to 300 nm. Thissubstantially matched the particle diameter distribution of the primaryparticle group of hydroxyapatite (HAp) obtained in Example 3. Acoefficient of variation of particle diameter was 17%, showing that thesintered particle group of hydroxyapatite (HAp) had a uniform particlediameter (narrow particle size distribution). FIG. 13 represents ascanning electron micrograph of the sintered particle group ofhydroxyapatite (HAp) obtained in Example 3. By performing reactions at95° C. in the primary particle generating step, a rod-like primaryparticle group of hydroxyapatite (HAp) was produced.

From the result shown in FIG. 11, the sintered particle group ofhydroxyapatite (HAp) obtained in Comparative Example 2 had a particlediameter of about 600 nm to 4000 nm. This suggests that the sinteredparticle group of hydroxyapatite (HAp) obtained in Comparative Example 2has formed secondary particles, with the primary particles randomlyfused together. A coefficient of variation of particle diameter was 53%,much greater than that of Example 3.

The foregoing results revealed that the rod-like sintered particle groupof hydroxyapatite (HAp) obtained in Example 3 was highly dispersive,with almost all (90%) of the particles dispersed as primary particles ofsingle crystal when suspended in a solvent, and that the rod-likesintered particle group of hydroxyapatite (HAp) obtained in Example 3had a nanometer size particle diameter of about 150 nm to about 300 nm,which were even more uniform (narrow particle size distribution).

Example 4

(Primary Particle Generating Step)

A flask was charged with 800 ml of 42 mmol/l calcium nitrate [Ca(NO₃)₂]aqueous solution that had been adjusted to pH 12 with 25% aqueousammonia. The solution was then heated to 80° C. in the atmosphere ofnitrogen. Over the period of 20 hours, the solution in the flask wassupplemented with 200 ml of 100 mmol/l diammonium hydrogenphosphate[(NH₄)₃HPO₄] that had been adjusted to pH 12 with 25% v/v aqueousammonia.

The product of reaction was separated and washed by centrifugation toobtain primary particles of hydroxyapatite (HAp). The primary particlegroups of hydroxyapatite (HAp) were dispersed in ethanol and particlesize distributions (distributions of particle diameters) were measuredby a dynamic light scattering method. FIG. 14 shows the result. For themeasurement of dynamic light scattering, the dynamic light scatteringphotometer DLS-6000 of Otsuka Electronics Co., Ltd. was used. Themeasurement was performed at room temperature, a 10 ppm particleconcentration, and a scattering angle of 90°. According to the resultshown in FIG. 14, the primary particle group of hydroxyapatite (HAp) hada particle diameter in a range of 350 nm to 600 nm. A coefficient ofvariation of the particle diameter was 17%.

(Mixing Step)

As the anti-fusing agent, calcium polyacrylate was used. In a 100 mlaqueous solution (pH 7) containing 0.5 g of polyacrylic acid (theproduct of ALDRICH, weight-average molecular weight 15,000 g/mol), 0.5 gof a primary particle group of hydroxyapatite (HAp) was dispersed toadsorb polyacrylic acid on the surface of the particles.

Next, 500 ml of calcium hydroxide [Ca(OH)₂] saturated aqueous solutionwas added to the dispersion so prepared, so as to deposit calciumpolyacrylate on the surface of the particles. The resulting precipitateswere collected and were dried under reduced pressure at 80° C., so as toobtain mixed particles.

(Sintering Step)

The mixed particles were placed in a crucible and sintered therein for 1hour at 800° C. The heat decomposed calcium polyacrylate into calciumoxide [CaO]. After the sintering step, a 25% or greater proportion ofcalcium oxide [CaO] remained.

(Removing Step)

In order to more easily dissolve the anti-fusing agent in water, anaqueous solution of 50 mmol/l ammonium nitrate [NH₄NO₃] was prepared.The sintered particles were suspended in 500 ml of the aqueous solutionso prepared. This was followed by separation and washing bycentrifugation. The particles were further suspended in distilled water,and separated and washed again by centrifugation to remove theanti-fusing agent and ammonium nitrate and collect a sintered particlegroup of hydroxyapatite (HAp). Element analysis found that Ca/P ratio ofthe sintered particles of hydroxyapatite (HAp) was 1.72, confirming thatthe sintered particles of hydroxyapatite (HAp) were calcium-richapatite.

Comparative Example 3

For comparison, 0.5 g of primary particle group of hydroxyapatite (HAp)obtained in the primary particle generating step of Example 4 wereplaced in a crucible, and were sintered for 1 hour at 800° C. to obtaina sintered particle group of hydroxyapatite (HAp). That is, in thisexample, a sintered particle group of hydroxyapatite (HAp) was producedwithout calcium polyacrylate as the anti-fusing agent. Element analysisfound that Ca/P ratio of the sintered particles of hydroxyapatite (HAp)was 1.67, identifying the sintered particles of hydroxyapatite (HAp) asthe apatite with a stoichiometric composition.

Comparison between Example 4 and Comparative Example 3

The sintered particle groups of hydroxyapatite (HAp) were dispersed inethanol and particle size distributions (distributions of particlediameters) were measured by a dynamic light scattering method. FIG. 15shows the result for the sintered particle group of hydroxyapatite (HAp)obtained in Example 4, and FIG. 16 shows the result for the sinteredparticle group of hydroxyapatite (HAp) obtained in Comparative Example3.

It can be seen from the result shown in FIG. 15 that the sinteredparticle group of hydroxyapatite (HAp) obtained in Example 4 had aparticle diameter in a range of 350 nm to 600 nm. This substantiallymatched the particle diameter distribution of the primary particle groupof hydroxyapatite (HAp) obtained in Example 4. A coefficient ofvariation of particle diameter was 15%, showing that the sinteredparticle group of hydroxyapatite (HAp) had a uniform particle diameter(narrow particle size distribution). FIG. 17 represents a scanningelectron micrograph of the sintered particle group of hydroxyapatite(HAp) obtained in Example 4. By performing reactions at 80° C. in theprimary particle generating step, a rod-like (bar-like) primary particlegroup of hydroxyapatite (HAp) was produced.

From the result shown in FIG. 16, the sintered particle group ofhydroxyapatite (HAp) obtained in Comparative Example 3 had a particlediameter of about 250 nm to 4000 nm. This suggests that the sinteredparticle group of hydroxyapatite (HAp) obtained in Comparative Example 3has formed secondary particles, with the primary particles randomlyfused together. A coefficient of variation of particle diameter was 65%,much greater than that of Example 4. FIG. 18 represents a scanningelectron micrograph of the sintered particle group of hydroxyapatite(HAp) obtained in Comparative Example 3. It can also be seen from FIG.18 that the sintered particle group of hydroxyapatite (HAp) obtained inComparative Example 3 formed secondary particles, with the primaryparticles randomly fused together.

Next, measurement was made as to the specific surface areas of thesintered particle groups of hydroxyapatite (HAp) obtained in Example 4and Comparative Example 3. The measurement was made according to anitrogen gas adsorption method, using the high-speed specific surfacearea/pore size distribution measurement device NOVA-1200 (Yuasa IonicsInc.). The nitrogen gas adsorption method refers to a method in which aninert gas with a known adsorption area is adsorbed on particle surfacesat liquid nitrogen temperature, and a specific surface area of thesample is determined from the quantity of the absorbed gas (seeBrunauer, S., Emmett, P. H. and Teller, E. Adsorption of gases inmultimolecular layers. J. Am. Chem. Soc., 60, 309-319 (1938)). Briefly,after deaerating a sample in vacuum for 10 minutes, a specific surfacearea of the sample was determined according to a BET multi-plot method,from a ratio of equilibrium pressure without the sample and equilibriumadsorption pressure with the sample as determined by a pressuretransducer.

FIG. 19 represents specific surface areas of the primary particle groupand sinter particle group of hydroxyapatite (HAp) obtained in Example 4,and a specific surface area of the sintered particle group ofhydroxyapatite (HAp) obtained in Comparative Example 3. In FIG. 19, thenotation “**” means there is a significant difference for a significancelevel less than 1%, and “ns” means there is no significant difference.

The sintered particle group of hydroxyapatite (HAp) obtained inComparative Example 3 had fused particles, and therefore there was asignificant reduction in specific surface area as compared with theprimary particle group before sintering. The sintered particle group ofhydroxyapatite (HAp) obtained in Comparative Example 3 had a specificsurface area of about 15 m²/g. The sintered particle group ofhydroxyapatite (HAp) obtained in Example 4 had a large specific surfacearea of about 20 m²/g, the same as the specific surface area of theprimary particle group before sintering.

It was found from the foregoing results that the rod-like sinteredparticle group of hydroxyapatite (HAp) obtained in Example 4 was highlydispersive, with almost all of the particles dispersed as primaryparticles of single crystal when suspended in a solvent, and that therod-like sintered particle group of hydroxyapatite (HAp) obtained inExample 4 had a uniform particle diameter of about 350 nm to 600 nm(narrow particle size distribution) and a large specific surface area.

INDUSTRIAL APPLICABILITY

A ceramic particle group according to the present invention can besuitably used as, for example, a medical material, a chromatographyfiller, a support for immobilizing bacteria or yeasts, as well as anadsorbent such as a deodorizer. The invention is therefore applicable ina wide range of fields, including medical industry using medicalmaterials, analytical science where chromatography is performed, as wellas food and pharmaceutical industries. The invention is also applicableto cosmetic additives, alternative building materials of asbestos, andindustrial materials.

1. A ceramic particle group comprised of granular ceramic particles,wherein the ceramic particles have a particle diameter in a range of 10nm to 700 nm, and wherein a coefficient of variation of particlediameter of the ceramic particles is no greater than 20%.
 2. A ceramicparticle group comprised of granular ceramic particles, wherein amajority of the ceramic particles in the ceramic particle group aremonocrystalline primary particles, which are either primary particles ofsingle crystal, or a cluster of primary particles of single crystal thatare held together by ionic interactions.
 3. A ceramic particle group asset forth in claim 2, wherein a proportion of the monocrystallineprimary particles contained in the ceramic particle group is no lessthan 70%.
 4. A ceramic particle group as set forth in claim 2, whereinthe ceramic particles have a particle diameter in a range of 10 nm to700 nm.
 5. A ceramic particle group as set forth in claim 2, wherein acoefficient of variation of particle diameter of the ceramic particlegroup is no greater than 20%.
 6. A ceramic particle group as set forthin claim 1, wherein the ceramic particles comprise sintered particles ofcalcium phosphate.
 7. A ceramic particle group as set forth in claim 1,wherein the ceramic particles comprise sintered particles ofhydroxyapatite. 8-19. (canceled)
 20. A chromatography filler, which usesa ceramic particle group of claim
 1. 21. A dental or medical material,which uses a ceramic particle group of claim
 1. 22. A cosmetic additivewhich uses a ceramic particle group of claim
 1. 23. A ceramic particlegroup as set forth in claim 2, wherein the ceramic particles comprisesintered particles of calcium phosphate.
 24. A ceramic particle group asset forth in claim 2, wherein the ceramic particles comprise sinteredparticles of hydroxyapatite.
 25. A chromatography filler, which uses aceramic particle group of claim
 2. 26. A dental or medical material,which uses a ceramic particle group of claim
 2. 27. A cosmetic additivewhich uses a ceramic particle group of claim
 2. 28. A building material,which uses a ceramic particle group of claim
 1. 29. A building material,which uses a ceramic particle group of claim
 2. 30. An industrialmaterial, which uses a ceramic particle group of claim
 1. 31. Anindustrial material, which uses a ceramic particle group of claim 2.